Ventricular hypertrophy due to chronic pressure overload is accompanied in experimental animals, by electrophysiolgic dysfunction, and is often associated clinically with progressive heart failure and/or sudden death due to arrhythmias. The basis for the progression form overload to electrical dysfunction and arrhythmias remains unclear. Our laboratory has been studying the relationships between experimental chronic pressure overload and electrophysiological dysfunction in hypertrophied ventricular tissue, including the mechanism of arrhythmias in normal and hypertrophied hearts. The results lead to the suggestion that endocardial cells on the ventricular free wall are the first cardiac cells to be affected by pressure overload, and that consequent chronic differences in regional electrophysiology of the left ventricle, especially action potential duration and refractoriness, underlie serious ischemia-induced electrophysiologic disturbances in the hypertrophied heart. Alteration of cellular K+ currents may be responsible for both action potential prolongation in chronic pressure overload and the enhanced arthythmogenicity during acute ischemia in the hypertrophied ventricle. To examine these hypotheses, three integrated specific aims and sets of experiments are outlined: 1. To characterize electrophysiologic properties of normal and hypertrophied subendocardial and subepicardial cells using preparations of isolated cells, and intact ventricles retaining important cellular architecture; 2. To compare the electrophysiologic responses of isolated and in situ normal and hypertrophied endo- and epicardial cells during acute ischemia; and 3. to determine the mechanisms underlying the changes in action potential duration of hypertrophied myocardium during ischemia and exposure to a prototype antiarrhythmic drug, quinidine. Methodology includes production of renovascular hypertension and conventional microelectrode technology; patch clamping of isolated hypertrophied myocytes is used to determine the role of unitary ATP-sensitive K+ channels in their ischemic response. The use of combined single cell and whole tissue approaches to study electrophysiologic changes will elicit information not obtainable by either technique alone. Collectively, the experiments will distinguish regional mechanisms of electrical dysfunction of the pressure overloaded-hypertrophied heart and provide a mechanistic basis for both understanding the apparent propensity of such hearts for enhanced arrhythmic activity and the pharmacologic management of ischemic arrhythmias.